Although the healthy CNS was historically assumed to be immune-privileged, a paradigm shift in the field of neuroimmunology has occurred in the last 10 years due in large part to the discovery that classical immune molecules, including major histocompatibility complex I (MHCI) proteins are expressed in the developing and adult brain. MHCI plays a wide range of important roles in development and plasticity, including limiting the establishment and strength of cortical connections. MHCI molecules have also been implicated in the pathogenesis of several neurodevelopmental psychiatric disorders, including schizophrenia (SZ) and autism spectrum disorders (ASD). In fact, genes within the MHC locus show the most reproducible and significant genome-wide association with SZ of any genes to date and MHCI molecules are also attractive candidates for mediating the effects of a systemic immune response on the developing brain, which is a risk factor for both SZ and ASD. However, despite this accumulating evidence for the importance of MHCI in the brain, almost nothing is known about the cellular and molecular mechanisms that mediate its effects. The central goals of this proposal are to: (i) determine the mechanisms that mediate the ability of MHCI to negatively regulate synapse formation and strength and (ii) identify how neuronal MHCI is regulated by immune dysregulation during gestation to alter cortical connections and cause disease in offspring. These goals will be accomplished using immunocytochemistry, biochemistry, structure-function analysis, time-lapse imaging, a novel long-term imaging assay, and whole-cell patch-clamp recording, through the following three specific Aims. (1) To identify the cellular and molecular mechanisms that mediate the function of postsynaptic MHCI in regulating the initial establishment of cortical connections. (2) To determine the function for MHCI molecules in the axon and presynaptic terminal during the establishment of cortical connections. (3) To identify the immune molecules and signaling pathways that act upstream of MHCI to regulate its expression and function during development and in disease. Results from this project will increase our understanding of how MHCI regulates brain development and function, thereby providing critical insight into how it might contribute to the pathogenesis of neurodevelopmental disorders. Identification of the signaling cascades upstream and downstream of MHCI has the potential to provide fresh insight into the molecular mechanisms underlying ASD and SZ and to reveal innovative and unexpected new targets for therapeutic intervention aimed at rescuing synaptic defects in these disorders.